Loss of recall (memory) is an essential component of general anesthesia, yet the mechanisms underlying this important effect remain unknown. Failure to block recall during anesthesia continues to be a health care problem-over 40,000 incidents of recall are reported annually in the United States. Experiments outlined in the proposed research will investigate anesthetic effects on Long Term Potentiation (LTP) of synaptic transmission, as a cellular basis for anesthetic-induced loss of recall. Mechanisms of action leading to a block of LTP will be investigated using electrophysiological recordings and specific pharmacological probes to isolate the synaptic and molecular targets for three widely used agents: isoflurane, propofol and midazolam. Experiments will be conducted using rat hippocampal brain slices and the well characterized Schaffer-collateral fiber to CA 1 pyramidal neuron synaptic circuit-the best studied synapse for LTP in the brain. The hippocampus is essential for learning and memory in humans and animals and LTP is the leading candidate for a cellular basis of learning in hippocampal cortex. Three Specific Aims will be undertaken in the proposed research: 1) To determine the effective concentration range for anesthetic-induced block of LTP. 2) To determine the involvement of GABA and glutamate-mediated synapses in anesthetic-induced block of LTP. 3) To determine whether postsynaptic actions at or downstream from NMDA receptors contribute to the anesthetic-induced block of LTP. It has not been possible to undertake experiments of this nature before now, because studies of anesthetic concentrations required to block recall, in vivo, have only recently appeared in the literature. Results from our research will provide a quantitative analysis of anesthetic concentrations needed to block LTP, and will determine the mechanisms of action which lead to this block. An understanding of the mechanisms of anesthetic-induced block of LTP could lead to the development of highly targeted agents for producing loss of recall during anesthesia-this could minimize undesirable side effects produced by anesthetics in current use. Preliminary results from our laboratory indicate that isoflurane blocks LTP at concentrations which are indistinguishable from those that block recall in humans, and considerably lower than those needed to block synaptic transmission.